PROJECT SUMMARY Strains of Escherichia coli are normal inhabitants of the lower gastrointestinal tract in humans and other animals. While many E. coli strains exist within the host as non-threatening commensal organisms, some acquire pathogenic characteristics enabling them to initiate disease. Strains of Extraintestinal Pathogenic E. coli (ExPEC) frequently colonize both humans and domesticated animals, causing a number of important diseases including urinary tract infections (UTIs), neonatal meningitis, and sepsis. These infections affect many millions each year in the USA, representing an enormous problem in terms of morbidity, high medical costs, and mortality. The combined medical, agricultural, and economic burden of ExPEC-related infections is escalating as antibiotic resistant strains become increasingly common. Especially troubling is the rampant global dissemination over the past several years of the ST131 clonal group of ExPEC strains, many of which are resistant to multiple frontline antibiotics. ST131 and other ExPEC strains can be transmitted between hosts via fecal-oral routes, and ExPEC colonization of the gastrointestinal tract is thought to be a key stage in the infectious life cycle of these pathogens. However, the mechanisms and consequences of gut colonization by ExPEC remain for the most part undefined. We have found that ST131 and other ExPEC isolates can effectively colonize and persist within the adult mouse intestinal tract, ousting non-pathogenic commensal and probiotic E. coli strains. In addition, our preliminary work indicates that ST131 isolates can persist within the intestines even in the face of antibiotic treatments that should eradicate the pathogens. The research outlined here will delineate the mechanisms by which ST131 and other ExPEC isolates are able to colonize and persist within the gut in the face of both natural defenses and antibiotics. This work may also help explain the success of pandemic ST131 isolates, while elucidating new strategies to combat these pathogens before they are able to disseminate and cause disease at sites beyond the intestinal tract.